默克的骨转新药：组织蛋白酶K抑制剂Odanacatib

2012年7月11日，默沙东（Merck & Co）周三表示，将结束有关其骨质疏松症药物odanacatib的一项III期临床试验，因为有明确证据表明，该实验性药物确实有效。

Odanacatib是一种组织蛋白酶K抑制剂，目前处于预防骨质疏松症的III期临床试验阶段，先前已获得了令人振奋的II期临床数据。

默沙东称，该试验的结束是基于一个独立监察委员会对早期实验数据的分析。试验中，通过与安慰剂比较，评估了odanacatib在减少患骨质疏松症的绝经后女性骨折风险的有效性，同时也评估了药物的安全性。默沙东称，监察委员会还确定了有关该药可能的一些安全问题。

默沙东称，将继续在扩展研究中评估odanacatib的有效性及安全性，并计划于2013年上半年向美国、欧盟、日本提交odanacatib的上市审批申请。

骨质疏松是一种骨胳机能紊乱的疾病，主要表现为患者的骨密度下降，骨折危险性升高。由于骨质丢失是一种渐进和无痛的过程，因此，只有在发生骨折后，骨质疏松才能被诊断出来，这就给对骨质疏松患者人群的预测带来了挑战。

在美国，40岁以上的人群中，每两位妇女中就有1位妇女，每4名男性中就有1名男性遭受与骨质疏松有关的骨折的折磨。全球有2亿人将遭受骨质疏松的折磨。

Merck reported it recently received and is reviewing safety and efficacy data from the pivotal Phase III trial of odanacatib, the company’s investigational medicine for osteoporosis. As previously indicated, the company has been conducting a blinded extension of the trial in approximately 8,200 women, which will provide additional safety and efficacy data. Merck now anticipates that it will file applications for approval of odanacatib in 2014 with additional data from the extension trial, rather than filing in the first half of 2013. The company continues to believe that odanacatib will have the potential to address unmet medical needs in patients with osteoporosis.

默克的骨转新药：组织蛋白酶K抑制剂Odanacatib

All of the women studied had received alendronate (Fosamax) for at least 3 years.

Patients could have been off the bisphosphonate for up to 3 months prior to enrollment, but many switched directly over to odanacatib, said study coauthor Dr. Albert Leung, executive director of clinical research at Merck Research Laboratories.

"This drug has the potential to give additional benefits when [patients] have been treated with alendronate for a number of years and the treatment effect has reached a plateau and they may need a different treatment," he said in an interview.

In July 2012, a pivotal 16,731-patient, phase III trial of odanacatib was stopped early after an interim analysis showed a "favorable benefit-risk profile" for fracture risk reduction in postmenopausal women with previously untreated osteoporosis.

"It could be quite a population that may benefit from this drug," Dr. Leung remarked.

The study's data monitoring committee, however, flagged safety concerns in "certain selected areas" for further follow-up. Those safety risks have not been identified as the trial is still closing, but will be monitored along with efficacy in a double-blind, placebo-controlled, extension trial going out to 5 years of treatment, he said.

Merck, which plans to submit regulatory applications for odanacatib in the United States and Europe in the first half of 2013, has high hopes for odanacatib despite competition from generic drugs because of its novel mechanism of action.

Odanacatib inhibits cathepsin K, the primary protease in osteoclasts that breaks down bone collagen during bone resorption. Unlike traditional antiresorptive drugs like bisphosphonates, however, odanacatib does not interfere with the function of the entire osteoclast osteoclast /os·teo·clast/ (os´te-o-klast?)
1. a large multinuclear cell associated with absorption and removal of bone.

2. an instrument used for osteoclasis.  or reduce the number of osteoclasts. This characteristic is important, as osteoclasts secrete signaling factors to stimulate osteoblasts, the cells responsible for bone formation. As a result, there is greater bone formation with odanacatib, Dr. Leung explained.

The phase II trial enrolled women at least 60 years of age (mean 71 years) with a BMD T score of -2.5 to more than -3.5 at any hip site without a prior fragility fracture or those with a history of fragility fracture (except hip fracture), and a BMD T score of -1.5 and more than -3.5 at any hip site.

The women were randomly assigned to odanacatib 50 mg once weekly or placebo for 24 months, as well as 5,600 IU of vitamin D3 per week and calcium at dosages up to 1,200 mg/ day. The study was not powered to assess fractures.

At 24 months, the change in BMD at the lumbar spine was significant at 2.28% for odanacatib vs. a loss of 0.30% with placebo (P less than .001).

BMD change was not significant at the distal forearm, with losses of 0.92% vs. 1.14%, respectively.

As expected, urinary collagen type I cross-linked N-telopeptide, a biomarker of bone resorption, increased with placebo, compared with a significant 47% decrease with odanacatib.

The bone formation marker, serum type I procollagen, rose inexplicably with placebo, but this increase was surpassed by a significant gain of 31.2% with odanacatib.

Most unexpected, however, was an increase in the resorption resorption /re·sorp·tion/ (re-sorp´shun)
1. the lysis and assimilation of a substance, as of bone.

2. reabsorption.

--------------------------------------------------------------------------------

re·sorp·tion
n.  marker collagen type I cross-linked C-telopeptide (sCTx) with once-weekly odanacatib.

Dr. Leung said the finding appears to correlate with the bone density changes because sCTx levels remained relatively stable during the first 12 months of treatment before rising in the second year of the study.

Finally, adverse events were similar in both groups. The most common adverse events in the odanacatib and placebo arms were urinary tract infection urinary tract infection (UTI),
n infection in one or more of the structures that make up the urinary system. Occurs more often in women and is most commonly caused by bacteria.  (11.5% vs. 16.5%, respectively), back pain (11.5% vs. 9.9%), arthralgia (9% vs. 9.9%), and fractures (4.9% vs. 13.2%).

Treatment discontinuation rates due to adverse events were 9% vs. 3.3%, he said.

这个是个难得的骨转好药！
1、口服，不用静滴。
2、不引起骨坏死。
双磷酸盐类、地诺单抗引起骨坏死的副作用是随着用药时间增加而增加的，所以医师建议最多用1年。

有操作性， 用量小，口服。

很好啊，口服的。

期待骨转新药

Merck公司宣布其研制的治疗骨质疏松症新药odanacatib未能如期结束研究，研究人员称将对药物的安全性和有效性进行新的评估。就在2012年夏天时，Merck公司曾信心满满地宣布odanacatib可能会提前研制成功，一旦上市每年的销售额有望达到25亿美元。  　　Merck公司宣布其研制的治疗骨质疏松症新药odanacatib未能如期结束研究，研究人员称将对药物的安全性和有效性进行新的评估。就在2012年夏天时，Merck公司曾信心满满地宣布odanacatib可能会提前研制成功，一旦上市每年的销售额有望达到25亿美元。

　　Merck公司表示，公司将再扩大招募8200名女性以检验odanacatib的安全性和有效性，研究进程因而推迟至2014年。公司股价也因此下跌。
　　最近一段时间，Merck公司的研究进程并不顺利，首先是公司研发的胆固醇药物Tredaptive因为安全性问题未能通过FDA审核迫使公司将其推广中心放在欧洲，而最近的研究表明，药物的有效性也存在疑问。其次是公司的安眠药Suvorexant也面临着巨大竞争。

不知什么时候能吃上非正版啊？